Benzoheterocyclic distamycin derivatives, process for preparing them, and their use as antitumor and antiviral agents

Abstract

Benzoheterocyclic distamycin derivatives of formula (I) wherein: n is 2, 3 or 4; A is O, S, or NR, wherein R is hydrogen or C 1 -C 4 alkyl; B is CH or N; R 1 is hydrogen or C 1 -C 4 alkyl; T is selected from; (i) formula (II) wherein: p is zero or 1; R 2 and R 3 are selected, each independently, from: hydrogen, C 1 -C 4 alkyl optionally substituted by one or more fluorine atoms, and C 1 -C 4 alkoxy; R 4 is C 1 -C 4 alkyl or C 1 -C 3 haloalkyl; X 1 is a halogen atom; and (ii) formula (III) wherein X 2 is a halogen atom; and pharmaceutically acceptable salts thereof, are described. Such compounds are useful as antineoplastic and antiviral agents. ##STR1##

What is claimed is: 
     
       1. A compound which is a benzoheterocyclic distamycin derivative of formula: ##STR19## wherein: n is 2, 3 or 4; A is NR, wherein R is hydrogen or C 1  -C 4  alkyl;   B is CH;   R 1  is hydrogen or C 1  -C 4  alkyl;   T is selected from: ##STR20## wherein: p is zero or 1; R 2  and R 3  are selected, each independently, from: hydrogen, C 1  -C 4  alkyl optionally substituted by one or more fluorine atoms, and C 1  -C 4  alkoxy; R 4  is C 1  -C 4  alkyl or C 1  -C 3  haloalkyl; X 1  is a halogen atom; and ##STR21## wherein X 2  is a halogen atom; or a pharmaceutically acceptable salt thereof.   
     
     
       2. A compound according to claim 1, wherein: n is 2 or 3;   A is NH or NCH 3  ;   B is CH;   R 1  is hydrogen;   T is a group of formula (II) according to item (i), wherein X 1  is chlorine or bromine; R 4  is ethyl, 2-chloroethyl or 2-bromoethyl; R 2  and R 3  are, each independently, hydrogen or methyl; p is zero or 1; or   T is a group of formula (III) according to item (ii), wherein X 2  is bromine or chlorine.     
     
     
       3. A compound according to claim 1, selected from: 3-[1-methyl-4[1-methyl-4[1-methyl-4[5-N,N-bis(2-chloroethyl)aminoindole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;   3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5-N,N-bis(2-chloroethyl)aminoindole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;   3-[1-methyl-4[1-methyl-4[1-methyl-4[5-N,N-bis(2-bromoethyl)aminoindole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;   3-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-bromoacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;   3-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-bromoacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;   3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5(α-bromoacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;   3-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-chloroacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;   3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5(α-chloroacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;   3-[1-methyl-4[1-methyl-4[1-methyl-4[5-[4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;   3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5-[4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;   3-[1-methyl-4[1-methyl-4[5-[4-N,N-bis(2-bromoethyl)aminobenzene-1-carboxamido]indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;   3-[1-methyl-4[1-methyl-4[1-methyl-5-[4-N,N-bis(2-bromoethyl)aminobenzene-1-carboxamido]indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;   3-[1-methyl-4[1-methyl-4[1-methyl-4[5-[4-N,N-bis(2-bromoethyl)aminobenzene-1-carboxamido]indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;   3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5-[4-N,N-bis(2-bromoethyl)aminobenzene-1-carboxamido]indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;   3-1-methyl-4[1-methyl-4[1-methyl-4[5-[4-N-ethyl-N(2-chloroethyl)aminobenzene-1-carboxamido]indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;   3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5-[4-N-ethyl-N(2-chloroethyl)aminobenzene-1-carboxamido]indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine; and the pharmaceutically acceptable salts thereof.     
     
     
       4. A pharmaceutical composition which comprises an effective amount of a compound as defined in claim 1 as an active principle, in association with one or more pharmaceutically acceptable carriers and/or diluents. 
     
     
       5. A method of inhibiting growth of a tumor or tumors in a mammal by administering a compound of formula (I) of claim 1 to the mammal. 
     
     
       6. The method of claim 5 wherein said tumor or tumors is a carcinoma. 
     
     
       7. The method of claim 6 wherein said carcinoma is selected from mammary carcinoma, lung carcinoma, bladder carcinoma, colon carcinoma. 
     
     
       8. The method of claim 5 wherein the mammal is a human. 
     
     
       9. A method of treating a viral infection by administering a compound of formula (I) of claim 1. 
     
     
       10. A process for producing a compound as defined in claim 1, which process comprises: (1)(a) reacting a compound of formula: ##STR22##  wherein n is 2, 3 or 4, with a compound of formula: ##STR23##  wherein: A is NR, wherein R is hydrogen or C 1  -C 4  alkyl; B is CH;   R 1  is hydrogen or C 1  -C 4  alkyl;   T is selected from: ##STR24##  wherein: p is zero or 1; R 2  and R 3  are selected, each independently, from: hydrogen, C 1  -C 4  alkyl optionally substituted by one or more fluorine atoms, and C 1  -C 4  alkoxy; R 4  is C 1  -C 4  alkyl or C 1  -C 3  haloalkyl; X 1  is a halogen atom; and ##STR25##  wherein X 2  is a halogen atom;   Y is hydroxy or a leaving group;     to obtain a compound of formula (I) as defined above; or:   (b) reacting a compound of formula: ##STR26##  wherein n, A, B, and R 1  are defined as above, with a compound of formula: ##STR27##  wherein X 1 , R 2 , R 3 , and R 4  are defined as above, and Y 1  is hydroxy or a leaving group;   or with a compound of formula: ##STR28##  wherein X 2  is as defined above, and Y 2  is hydroxy or a leaving group;   to obtain a compound of formula (I) as defined above, wherein T is a group of formula (II) according to item (i) with p equal to 1, or a group of formula (III) according to item (ii); or:   (c) reacting a compound of formula: ##STR29##  wherein p, n, A, B, R 1 , R 2 , and R 3  are defined as above, and R 5  is hydrogen or C 1  -C 4  alkyl, with ethylene oxide, so obtaining a compound of formula: ##STR30##  wherein p, n, A, B, R 1 , R 2 , and R 3  are defined as above, and R 6  is equal to R 5  when R 5  is C 1  -C 4  alkyl, or R 6  is equal to --CH 2  CH 2  --OH when R 5  is hydrogen;   and then reacting the compound of formula (IX) with a halogenating agent, to obtain a compound of formula (I) as defined above, wherein T is a group of formula (II) according to item (i) with p equal to zero or 1; and   (2) if necessary, converting the so obtained compound of formula (I) into a pharmaceutically acceptable salt thereof.